title: Interleukin-32: a new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis.
abstract: Interleukin 32 (IL-32) is a recently described proinflammatory cytokine that activates p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), thereby inducing proinflammatory cytokines such as IL-1β and tumor necrosis factor alpha (TNF-α). We investigated the role of IL-32 in patients with chronic hepatitis C virus (HCV) infection. Steady-state hepatic messenger RNA (mRNA) levels of IL-32 were determined in a cohort of 90 subjects; anti-IL-32 staining was used in a second cohort of 132 consecutive untreated chronic HCV patients. Correlations with histological features of steatosis, inflammation, and fibrosis were made. In vitro, endogenous IL-32 in monocytes and in the human hepatoma cell line Huh-7.5 were examined. The effects of IL-32-overexpression and IL-32-silencing on HCV replication were studied using HCV luciferase reporter viruses. There were highly significant positive associations between hepatic IL-32 mRNA expression and liver steatosis, inflammation, fibrosis, smooth muscle actin (SMA) area, and serum alanine aminotransferase (ALT) levels. IL-32 protein expression was positively associated with portal inflammation, SMA area, and ALT. In vitro, IL-1β and TNF-α significantly induced IL-32 expression in human Huh-7.5 cells. Alone, stimulation with interferon alpha (IFN-α) did not induce IL-32 expression in Huh-7.5. However, IFN-α exerted a significant additive effect on TNF-α-induced but not IL-1β-induced IL-32 expression, particularly in CD14+ monocytes. This effect was dependent both on NF-κB and Jak/STAT signaling. Viral infection of Huh-7.5 cells resulted in a significant (11-fold) induction of IL-32 mRNA expression. However, modulation of IL-32 in Huh-7.5 cells by overexpression or silencing did not influence HCV virus replication as determined by luciferase assays.
  
  
  CONCLUSIONS
  IL-32 is a novel proinflammatory cytokine involved in HCV-associated liver inflammation/fibrosis. IL-32 is expressed by human hepatocytes and hepatoma cells and its expression is regulated by proinflammatory stimuli.
authors.affiliation: Christian Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moschen
authors.forename: Teresa
authors.initials: T
authors.lastname: Fritz
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.forename: Ilka
authors.initials: I
authors.lastname: Rebhan
authors.forename: Oliver
authors.initials: O
authors.lastname: Bauhofer
authors.forename: Helen D
authors.initials: HD
authors.lastname: Barrie
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Powell
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Julie R
authors.initials: JR
authors.lastname: Jonsson
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
mesh_terms: D000328:Adult; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000502:physiology
chemical_list: C496971:IL32 protein, human; D016898:Interferon-alpha; D053583:Interleukin-1beta; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha